Cell cycle

The cell cycle, or cell-division cycle (CDC), is the series of events in a eukaryotic cell between one cell division and the next. Thus, it is the process by which a single-cell fertilized egg develops into a mature organism and the process by which hair, skin, blood cells, and some internal organs are renewed. A specialized form of cell division is responsible for cellular differentiation during embryogenesis and morphogenesis, as well as for the maintenance of stem cells during adult life.

The cell cycle consists of four distinct phases: G1 phase, S phase, G2 phase (collectively known as interphase) and M phase. M phase is itself composed of two tightly coupled processes: mitosis, in which the cell's chromosomes are divided between the two daughter cells, and cytokinesis, in which the cell's cytoplasm physically divides. Cells that have temporarily or reversibly stopped dividing are said to have entered a state of quiescence called G0 phase, while cells that have permanently stopped dividing due to age or accumulated DNA damage are said to be senescent. Some cell types in mature organisms, such as parenchymal cells of the liver and kidney, enter the G0 phase semi-permanently and can only be induced to begin dividing again under very specific circumstances; other types, such as epithelial cells, continue to divide throughout an organism's life.

The molecular events that control the cell cycle are ordered and
directional; that is, each process occurs in a sequential fashion and
it is impossible to "reverse" the cycle. There are two key classes of
regulatory molecules that determine a cell's progress through the cell
cycle: cyclins and cyclin-dependent kinases. Leland H. Hartwell, R. Timothy Hunt, and Paul M. Nurse won the 2001 Nobel Prize in Physiology or Medicine for their discovery of these central molecules in the regulation of the cell cycle.

Phases of the cell cycle

Schematic of the cell cycle. I=Interphase, M=Mitosis. The duration of mitosis in relation to the other phases has been exaggerated in this diagram

Although the various stages of interphase are not usually
morphologically distinguishable, each phase of the cell cycle has a
distinct set of specialized biochemical processes that prepare the cell
for entry into the next stage. It should be remembered that, throughout
interphase, the cell carries out its normal metabolic activities and is actively engaging in transcription and translation of its genome.

In G1 phase, the cell carries on its usual
metabolic activities while preparing to duplicate its DNA. These
preparations often include growing by increasing the amount of cytoplasm and the number of important organelles such as mitochondria. (This is particularly important in organisms and cell types that divide their cytoplasm unevenly, as in budding yeast.) In G1 a diploid cell (such as a human cell) has a complement of 2N chromosomes, where N is the gene copy number;
in sexually reproducing organisms this amounts to one chromosome
inherited from each parent. The actual quantity of DNA is described as
2c, where the "c" value is measured in picograms and 1c is equal to the
quantity of DNA in a single haploid genome. The end of G1 is
demarcated by a "point of no return" beyond which the cell is committed
to dividing; in yeast this is called START and in multicellular
eukaryotes it is termed the restriction point.

In S phase, the cell duplicates its DNA.

In G2 phase, the cell continues with growth and metabolism in preparation for undergoing mitosis. In this quantity of DNA within the cell has increased to 4c, but the cell is still considered diploid.

In M phase the cell segregates its chromosomes so that both daughter cells receive a total complement of 2N. The four stages of mitosis - prophase, metaphase, anaphase, and telophase
- also progress in a sequential and directional fashion, like the cell
cycle as a whole. Telophase, the final stage of mitosis, is accompanied
by cytokinesis; when the cytoplasm is completely divided, the cycle is
complete and the new daughter cells are said to be in G1
again. The exact mechanism of cytokinesis is highly organism- and cell
type-dependent; for example, in plant cells surrounded by a rigid cell wall, cytokinesis occurs via the formation of a cell plate, while animal cells are "pinched" in two by a ring formed from a structural protein called actin.

Although the illustration assigns the four stages of the cell cycle
roughly equal durations, a cell actually spends a very small amount of
its time in G2 phase, and even less time in M phase. The overall duration of the cell cycle depends on the organism and type of cell.

The term "post-mitotic" is sometimes used to refer to both quiescent
and senescent cells. Nonproliferative cells in multicellular eukaryotes
generally enter the quiescent G0 state from G1 and may remain quiescent for long periods of time, possibly indefinitely (as is often the case for neurons). This is very common for cells that are fully differentiated.
Cellular senescence is a state that occurs in response to DNA damage or
degradation that would make a cell's progeny nonviable; it is often a
biochemical alternative to the self-destruction of such a damaged cell
by apoptosis.

Cyclins and cyclin-dependent kinases

Cyclins and cyclin-dependent kinases
(CDKs) are the two critical classes of molecules in regulation of cell
cycle progression. Cyclins form the regulatory subunits and CDKs the
catalytic subunits of an activated heterodimer;
cyclins have no catalytic activity and CDKs are inactive in the absence
of a partner cyclin. When activated by a bound cyclin, CDKs perform a
common biochemical reaction called phosphorylation
that activates or inactivates target proteins to orchestrate
coordinated entry into the next phase of the cell cycle. Different
cyclin-CDK combinations determine the downstream proteins targeted.

Many of the genes encoding cyclins and CDKs are conserved
among all eukaryotes, but in general more complex organisms have more
elaborate cell cycle control systems that incorporate more individual
components. Many of the relevant genes were first identified studying
yeast, especially Saccharomyces cerevisiae; genetic nomenclature in yeast dubs many of these genes cdc (for "cell division cycle") followed by an identifying number, e.g., cdc25.
In the following discussion generic names such as "S cyclin" will be
used to maintain generality, with the understanding that this may refer
to one or to several homologous molecules in any given organism, and
that some organisms may combine multiple functions in one molecule.

Upon receiving a pro-mitotic extracellular signal, G1 cyclin-CDK complexes become active to prepare the cell for S phase, promoting the expression of transcription factors that in turn promote the expression of S cyclins and of enzymes required for DNA replication. The G1 cyclin-CDK complexes also promote the degradation of molecules that function as S phase inhibitors by targeting them for ubiquitination. Once a protein has been ubiquitinated, it is targeted for proteolytic degradation by the proteasome.

Active S cyclin-CDK complexes phosphorylate proteins that make up the pre-replication complexes assembled during G1 phase on DNA replication origins.
The phosphorylation serves two purposes: to activate each
already-assembled pre-replication complex, and to prevent new complexes
from forming. This ensures that every portion of the cell's genome
will be replicated once and only once. The reason for prevention of
gaps in replication is fairly clear, because daughter cells that are
missing all or part of crucial genes will die. However, for reasons
related to gene copy number effects, possession of extra copies of certain genes would also prove deleterious to the daughter cells.

Mitotic cyclin-CDK complexes, which are synthesized but inactivated during S and G2 phases, promote the initiation of mitosis by stimulating downstream proteins involved in chromosome condensation and mitotic spindle assembly. A critical complex activated during this process is a ubiquitin ligase known as the anaphase-promoting complex (APC), which promotes degradation of structural proteins associated with the chromosomal kinetochore. APC also targets the mitotic cyclins for degradation, ensuring that telophase and cytokinesis can proceed.

Checkpoints

A molecular surveillance system monitors the cell's progress through
the cell cycle and halts progression if extensive DNA damage has
occurred or if a key event, such as the attachment of a chromosome to
the mitotic spindle, has not occurred properly. These checkpoints
help to ensure that a cell divides only when it has completed all of
the molecular prerequisites for producing healthy daughter cells.

Three key stages of progression through the cell cycle involve the
degradation of signaling molecules and are therefore irreversible;
passage through these checkpoints not only "certifies" that the cell is
capable of proceeding to the next step, but also commits the cell to
that process. The restriction point that marks the transition from G1 to S phase is the first such transition; the others occur between metaphase and anaphase (the spindle checkpoint) and between anaphase and telophase when mitotic cyclins are degraded.

The full system of checkpoints also includes monitoring of the
cell's DNA for unrepaired damage and for successful completion of
replication.

There are four DNA-damage checkpoints regulated primarily by the protein p53: one during G1, one at the entry into S phase, one near the end of S phase, and one at the entry into M phase.

The unreplicated DNA checkpoint that occurs at the entry into M
phase ensures that the cell has successfully and completely replicated
its genome.

The spindle-assembly checkpoint occurs during anaphase and checks
that all chromosomes have successfully attached to the mitotic spindle.

The chromosome-segregation checkpoint in telophase ensures that the
chromosomes have properly migrated to the cell poles and that the cell
is ready for cytokinesis and exit from mitosis.

The DNA-damage checkpoint protein p53 has been implicated in a large number of human cancers
because its absence allows the cell to proceed into S phase with
unrepaired DNA damage that leads to mutations when the DNA replication
machinery misinterprets the damaged region or uses a lossy DNA repair
mechanism to avoid the more serious consequence of proceeding through
the cell cycle with a partially unreplicated genome. Very few of these
mutations would by themselves be troublesome, but their continued
accumulation in p53-deficient cell lineages produces a high likelihood
of introducing mutations in oncogenes,
many of which are associated with controlling cell division and
preventing unconstrained growth. p53 also serves as a mechanism to
induce apoptosis, or "cell suicide", in cases where the cell has sustained irreparably high amounts of DNA damage.